7ZWQ

Crystal structure of human BCL6 BTB domain in complex with compound 10

7ZWQ の概要

• エントリーDOI: 10.2210/pdb7zwq/pdb
• 分子名称: B-cell lymphoma 6 protein, ~{N}-[(2-fluorophenyl)methyl]-5-methyl-[1,2,4]triazolo[1,5-a]pyrimidin-7-amine, 1,2-ETHANEDIOL, ... (5 entities in total)
• 機能のキーワード: inhibitor, cancer, transcription
• 由来する生物種: Homo sapiens (human)
• タンパク質・核酸の鎖数: 1
• 化学式量合計: 17650.23

構造登録者

Rodrigues, M.J.,Le Bihan, Y.-V.,van Montfort, R.L.M. (登録日: 2022-05-19, 公開日: 2022-11-16, 最終更新日: 2024-01-31)

主引用文献

Pierrat, O.A.,Liu, M.,Collie, G.W.,Shetty, K.,Rodrigues, M.J.,Le Bihan, Y.V.,Gunnell, E.A.,McAndrew, P.C.,Stubbs, M.,Rowlands, M.G.,Yahya, N.,Shehu, E.,Talbot, R.,Pickard, L.,Bellenie, B.R.,Cheung, K.J.,Drouin, L.,Innocenti, P.,Woodward, H.,Davis, O.A.,Lloyd, M.G.,Varela, A.,Huckvale, R.,Broccatelli, F.,Carter, M.,Galiwango, D.,Hayes, A.,Raynaud, F.I.,Bryant, C.,Whittaker, S.,Rossanese, O.W.,Hoelder, S.,Burke, R.,van Montfort, R.L.M.
Discovering cell-active BCL6 inhibitors: effectively combining biochemical HTS with multiple biophysical techniques, X-ray crystallography and cell-based assays.
Sci Rep, 12:18633-18633, 2022

PubMed Abstract: By suppressing gene transcription through the recruitment of corepressor proteins, B-cell lymphoma 6 (BCL6) protein controls a transcriptional network required for the formation and maintenance of B-cell germinal centres. As BCL6 deregulation is implicated in the development of Diffuse Large B-Cell Lymphoma, we sought to discover novel small molecule inhibitors that disrupt the BCL6-corepressor protein-protein interaction (PPI). Here we report our hit finding and compound optimisation strategies, which provide insight into the multi-faceted orthogonal approaches that are needed to tackle this challenging PPI with small molecule inhibitors. Using a 1536-well plate fluorescence polarisation high throughput screen we identified multiple hit series, which were followed up by hit confirmation using a thermal shift assay, surface plasmon resonance and ligand-observed NMR. We determined X-ray structures of BCL6 bound to compounds from nine different series, enabling a structure-based drug design approach to improve their weak biochemical potency. We developed a time-resolved fluorescence energy transfer biochemical assay and a nano bioluminescence resonance energy transfer cellular assay to monitor cellular activity during compound optimisation. This workflow led to the discovery of novel inhibitors with respective biochemical and cellular potencies (IC) in the sub-micromolar and low micromolar range.

PubMed: 36329085
DOI: 10.1038/s41598-022-23264-z

実験手法

X-RAY DIFFRACTION (1.65 Å)